Production of pyridine-carboxylic acids



Patented July 18, 1950 PRODUCTION OF PYRIDINE-CARBOXYLIC ACIDS WillemFrederik Engel and llan Hoog, Amsterdam, Netherlands, assignors to ShellDevelopment Company, San Francisco, Calif., a corporation of Delaware NoDrawing. Application January 30, 1948, Se-

rial No. 5,498. Inthe Netherlands February This invention relates to animproved process for. the production of pyridine-carboxylic acids fromheterocyclic nitrogen compounds containing.

a pyridine nucleus substituted by an oxidizable organic groupingattached to the nucleus by one or more carbon-to-carbon linkages andcapable of being oxidized to a carboxylic group. The invention relatesmore particularly to theproduction of pyridine-carboxylic acids fromalkyl' substituted pyridine compounds. A particular aspect of theinvention relates to the production of nicotinic acid frombeta-substituted alkyl pyridine compounds.

It has been disclosed heretofore that pyridinecarboxylic acids areproduced by the oxidation of alkyl substituted pyridines. Suchprocesses, as

disclosed heretofore, consist, for example, of the oxidation of thealkyl pyridine with the aid of aqueous permanganate solutions, nitricacid or solutions of chromic acid in sulfuric acid. These methods have,however, proven themselves highly impractical due to the relatively lowyields obtained therewith and the complexityand-difii-J culties inherentin the operative steps involved. These difficulties have been obviatedto some degree by the utilization of a process involving the oxidationof the alkyl substituted pyridine in the form of its salt with the aidof a halogen. Such a process, however, still is handicapped by seriousdisadvantages militating against eflicient large scale operation. Thesedifliculties include relatively low yields and a complexityof operativesteps. necessity in such processes as disclosed heretofore for theconversion of any unconverted pyridine compound, generally present inthe form. of'its salt, to relatively pure alkyl pyridine before itsreturn to the reactionzone. Since the conversions, per pass in such aprocess as disclosed heretofore are low, the conversion of 3-methylpyridine to nicotinic acid generally being of the order of'only about19%, the substantial amounts of material! which must be subjected tohighly complex oper- 3 Claims. (01. 260-2955) The latter difficulty isoccasioned by-the ative steps to enable their conversion to relativelypure alkyl pyridine prior to recycling to the reaction zone, results indetracting materially from practical operation of the process.

It is an object of the present invention to provide an improved processfor the more eliicient production of pyridine-carboxylic acids fromheterocyclic nitrogen compounds containing a pyridine nucleussubstituted by an oxidizable organic grouping attached to the nucleus byone or more carbon-to-carbon linkages and capable of being oxidized to acarboxylic. group enabling the attainment of a high yield ofpyridine-carboxylic acid with a minimum of operative steps.

A more particular object of the invention is the provision of animproved process enabling the more efiicient production of pyridine-canboxylic acids from alkyl substituted pyridine compounds enabling theobtaining of high yields with a minimum of operative steps.

Still another object of the invention is the provision of an improvedprocess enabling the more efiicient production of pyridinemonocarboxylic acids from methyl substituted pyridine compounds enablingthe attainment of high yields with a minimum of operative steps.

A still more particular object of the invention is the provision of animproved process for the production of nicotinic acid frombeta-substituted alkyl pyridine compounds enabling the attainment ofhigh yields with a, minimum of operative steps. Other objects andadvantages of the invention are apparent from the following detaileddescription thereof.

In accordance with the process of the invention a heterocyclic nitrogencompound containing a pyridine nucleus substituted byan oxidizableorganic grouping attached to the nucleus by one or more carbon-to-carbonlinkages and capable of being oxidized to a carboxylic group issubjected to an elevated temperature in an aqueous medium and in'thepresence of a free halogen in a reaction zone, and pyridine carboXylicacids are removed therefrom substantially as rapidly as formed. In apreferred method of executing the invention a portion of the reactionmixture is continuously Withdrawn from the reaction zone,pyridine-carboxylic acids are removed from the portion thus withdrawn,and the entire remaining portion of the Withdrawn reaction mixture, freeof any substantial amount of carboxylic acids, is returnedas such to thereaction zone. It has been found that such continuous removal of thepyridine-carboxylic acids from the reactionmixture substantially asrapidly as formed, results in the attainment of increased yields andenables the continuous recycle of substantially all of the remainingreaction mixture directly to the reaction zone, thereby obviating thecomplexity of operative steps heretofore resorted to in processeslimited to the recycling of only relatively pure alkyl pyridines.

Pyridine compounds oxidized to pyridine-carboxylic acids in accordancewith the invention comprise-as a. broad class the heterocyclic nitrogencompounds containing a pyridine nucleus substituted by an oxidizableorganic grouping attached to the nucleus by one or more carbon-tocarbonlinkages and capable of being oxidized to a carboxylic group. Members ofthis class include the salts of alkyl substituted Dyridines obtained,for example, by the reaction of an alkyl substituted pyridine with anyacid capable of forming a salt therewith. Examples of the alkylsubstituted pyridines comprise the alkyl pyri dines containing one ormore alkylgroups linked by carbon-to-carbon linkage to the pyridinenucelus. Particularly desirable alkyl pyridines comprise the methylpyridines such as, for exam-' ple, 2-methyl pyridine, 3-methyl pyridine,4- methyl pyridine, 2,6-dimethyl pyridine, 2,4-dimethyl pyridine, and2,4,6-trimethyl pyridine. Examples of salts of the alkyl pyridines.comprise the hydrochlorides, the hydrobromides, sulphates, acetates,etc. Particularly preferred are the alkyl pyridine hydrohalides, such asalkyl pyridine hydrochloride, alkyl pyridine hydrobromide, etc. obtainedby the interaction of an alkyl pyridine such as, for example, a methylpyridine, with the halogen acid. The following detailed description Ofthe invention will be made with particular reference to methylpyridinehydrochloride as the preferred pyridine-compounds containing anoxidizable substituent group which are subjected to the conditionsresulting in the obtaining of pyridine-carboxylic acids. It is to beunderstood, however, that this is done with no intent to limit the scopeof the invention to the use of only these particularly referred to alkylpyridine compounds as starting materials.

The alkyl pyridine hydrochloride such as, for example, a methylpyridinehydrochloride, is brought into contact with a free halogen at anelevated temperature in the presence of water in an oxidation zone.Suitable charge material tov the oxidation zone comprises the aqueousmethylpyridine hydrochloride-containing mixture obtained by the reactionof a methylpyridine with aqueous hydrochloric acid. Any of the membersof the halogen group may be employed as the free halogen in oxidizingthe methylpyridine hydrochloride to the corresponding pyridinecarboxylic.

ably in the range of from about 80 to about 1509 0., are employed in theoxidation of the methylpyridine salt to the corresponding pyridine-carboxylic acid. The reaction may be executed at atmospheric sub orsuperatmospheric pressures.v

The oxidation with the free halogen employed may be carried out in thepresence of halogenation or oxidation catalysts and/or activatingradiations such as ultraviolet light.

Under the above-defined conditions conversion of the alkyl pyridine saltto the corresponding pyridine-carboxylic acid will take place. Theaccumulation of substantial amounts of hydrogen halide within thereaction zone is preferably avoided. Removal of hydrogen halide may bebrought about by adding to the charge, or by separately introducin intothe reaction zone, a hydrogen halide accepting material, for example, analkaline compound suchas sodium carbonate, calcium carbonate or thelike. may also be comprised in the charge, or may be separatelyintroduced into the reaction zone, to.

dine hydrochloridecapable.of "undergoingfurther;

Alkyl pyridinev 4 conversion to the corresponding pyridine-carboxylicacid reaction product. At least a part of the alkyl pyridine thusadditionally introduced into the oxidation zone of the system may becomprised in the products recycled as described more fully below, and/ormay consist of unreacted alkyl pyridine contained in the alkyl pyridinehydrochloride charge to the oxidation zone.

It has now been found that the pyridinecarboxylic acid reaction productexerts a marked ill" retarding eiTect upon the rate of reaction so thatthe presence of relatively small amounts thereof in the reaction zonewill prevent its further formation. Its accumulation within the reactionzone in any substantial amounts will therefore generally prevent theobtaining of conversions per pass of a magnitude commensurate withefficient, large scale, practical operation. It has now further beenfound that removal of the pyridinecarboxylic acid reaction. product fromthe reactants enables the reaction toproceed with substantially initialvelocity and that, quite contrary to that held heretofore, noadverseeflect is encountered by retaining in, or recycling. to, thereaction zone the remaining reaction mixture, as'such, in its entirety.In accordance with the invention the pyridine-carboxylic acid reactionboxylic acid upon the yield obtained, and the substantial advantageobtained by avoiding its r accumulation in'the reaction mixture isevidenced by the following example:

Example Three-methylpyridine hydrochloride was prepared by adding 93parts by weight of 3-methylpyridine (beta-p-icoline) to parts'by weightof- 39 %"hydrochloric acid. Chlorine was introducedinto the aqueous3'-methylpyridine hydrochloride thus obtained, at a temperature of aboutC. andwhile subjected to ultraviolet rays. The conversion of3-methylpyridine hydrochloride to betapyridine-carboxylic acid(nicotinic acid) was found to be 14.7% after a reaction time of 8 hoursduration. At-the end of' 15 hours the conversion was still only 16.0%.

In a repetition of the experiment under substantially identicalconditions a conversion of 3- methylpyridine hydrochloridet'obetapyridinecarboxylic acid of 14.5% was obtained after areactiontime of 7 hours. The reaction mixture was then cooled to 0 C. tocrystallize the betapyridine-carboxylic acid produced.pyridine-carboxylic acid was separated from the cooled' reaction mixtureby filtration and the filtrate again subjected to substantially theidentical oxidation reaction conditions employed in the precedingoperation for an additional 6 hours. It was found that an additionalconversion of B-methylpyridine hydrochloride to betapyridine-carboxylicacid of 14.3% had been obtained.

It is thus seen that in the operation wherein removal ofbeta-pyridine-carboxylic acid reactionproduct' was not resorted to aconversion in: excess'of 16.0% could: not be obtained, whereas in thesecond operation wherein intermediate re:

moval of the beta-pyridine-carboxylic acid from. the: reactants wasresorted. to.a totalconversiorr- The adverse effect of the accumulatedpyridine-cab The betatoi beta-pyridine-carboxylic acid or as high as28.8% was obtained in a period of 13 hours.

A particular advantage of the invention resides in the ability torecycle to the reaction zone substantially all of the reaction productsremaining: after separating the pyridine-carboxylic acid therefrom. .Theprocess of the invention therefore enables the substantially completeconversion of the alkyl-pyridine salt'charged to the system to thedesired pyridine-carboxylic acid witho'ut ne'ed to resort to the complexoperative procedure heretofore resorted to involving the separation ofunconverted alkyl pyridine salt from the remaining complex reactionmixture in the formof relatively pure alkyl pyridine before recycling.The invention thus enables the eficient conversion of alkyl pyridines tothe corresponding pyridine-carboxylic acids not only withsubstantialincrease in yield but with a minimum of operative steps.

In a preferredmethod of carrying out continuously the process of theinvention, an alkyl pyridine such as, for example, a methylpyridine, iscontacted with aqueous hydrochloric acid to result in the formation ofaqueous methylpyridine hydrochloride. The resulting aqueous methylpyridine hydrochloride is brought into contact with a free halogensuch as chlorine, at the reaction temperature in a, reaction zone. Aportion of the reaction mixture is continuously withdrawn from thereaction zone. The portion thus withdrawn is freed ofpyridine-carboxylic acid reaction product, which generally will bepresent therein to at least a substantial degree in the form of thesalt, such as pyridine-carboxylic acid hydrochloride.

Separation of the pyridine-carboxylic acid reaction product from theportion of reaction mixture withdrawn from the reaction zone is effectedby any suitable means. Thus the separation may be effected by coolingthe portion withdrawn from the reaction Zone to a sufficiently lowtemperature to eifect the crystallization of the pyridinecarboxylic acidreaction product. Thus in the preparation of nicotinic acid from.3-methylpyridine hydrochloride a temperature of about0 C. has beenfound satisfactory. The solidified pyridine-carboxylic acid reactionproduct is sepa rated from the cooled reaction mixture by such means asfiltration, centrifuging or the like. The remaining portion of thereaction mixture, now free of any substantial amount ofpyridine-carboxylic acid reaction product, is returned as such, withoutfurther separation of products therefrom, to the reaction zone.Withdrawal of reactants from the reaction zone and its passage to thepyridine-carboxylic acid removal step is effected at a sufiicientlyrapid rate to avoid the accumulation to any substantial degree ofpyridine-carboxylic acid reaction product in the reaction zone.

A single reactor, provided with two consecutive zones, may be employed.In the first of said zones the alkyl pyridine, such as, for example amethylpyridine, and aqueous hydrochloric acid are introduced andconverted therein to methylpyridine hydrochloride. Products comprisingmethylpyridine hydrochloride are passed from the first of the zones intothe second zone of the reactor wherein they are subjected to theoxidation reaction temperatures in the presence of free chlorineseparately introduced therein. A portion of the methylpyridine chargemay be passed directly to the second zone of the reactor to functiontherein as the acceptor for the hydrogen chloride liberated during thereaction. Hydrogen chloride formed in the second or oxidation zone ofthe reactor may be recycled directly to the first zone of the reactorwherein the methylpyridine hydrochloride is formed. The invention is,however, in no wise limited tothe use of any specific type of reactor orreactors as the reaction zone. Thus separate reactors in communicationwith one another may be employed and the alkyl pyridine salt formationexecuted in one of the reactors and the alkyl pyridine salt oxidation inthe other.

The oxidation reaction may be executed in the liquid or vapor phase.When operating in the liquid phase the oxidation zone may comprise acolumn wherein the chlorine and methylpyridine hydrochloride are broughtinto countercurrent contact. Liquid, comprising unconverted reactantsand pyridineecarboxylic acid, is continuously drawn from the lower partof the column. Pyridine-carboxylic acid is removed from the liquid thusdrawn from the base of. the column and the remaining reactants,substantially free of pyridine-carboxylic acid, are recycled in theirentirety to the top of the column. Such continuous operation involvingthe continuous recycle of liquid from the base of the column to the topthereof, with removal of pyridinecarboxylic acid reaction product fromthe recycle stream, assures the continuous contact of reactantscomprising methylpyridine free of any substantial amount ofpyridine-carboxylic acid reaction product with the free halogen. Therebyassuring the obtaining of high yields of the desired pyridine-carboxylicacid with a minimum of operative steps.

A particular advantage of the invention resides in its ability to enablethe production, with substantially improved efficiency, of valuablenicotinic acid from beta-substituted alkyl pyridines such as3-methylpyridine, by the oxidation of the alkyl pyridines in the form oftheir salts under the conditions set forth herein. The product obtainedwill of course vary with the specific charge material employed. Thus thealkyl pyridine charged will be oxidized under the conditions set forthherein to the corresponding pyridine-carboxylic acid. ThusZ-methylpyridine, B-methylpyridine and l-methylpyridine are oxidized, inthe form of their salts to picoline acid, nicotinic acid, andisonicotinic acid, respectively. Utilization of a di-substituted alkylpyridine will result in the production of pyridinedicarboxylic acid.Thus utilization of a charge comprising 2,3-methylpyridine will resultin the obtaining of a product comprising quinolinic acid.

We claim as our invention:

1. The process for the production of nicotinic acid which comprisesheating an admixture of 3-methylpyridine hydrochloride, chlorine andwater at a temperature of about C., thereby converting said admixture toreaction products comprising nicotinic acid and unconverted3-methylpyridine hydrochloride, continuing said heating until aconversion of 3-methy1pyridine hydrochloride to nicotinic acid of about14% has been obtained, thereafter separating nicotinic acid from saidreaction products, and further heating said remaining reaction productsin the presence of added chlorine at a temperature of about 115 0.,thereby effecting the further conversion of at least a substantialamount of said unconverted 3-methylpyridine hydrochloride to nicotinicacid.

'2. The process for the production of nicotinic acid which comprisesheating an admixture of 3-methylpyridine-hydrochloride, chlorine andwater at a temperature of .from about 80 C. to about ,150 0., therebyconverting said admixture to reaction products comprising nicotinic acidand unconverted 3 -methylpyridine-hydrochloride, continuing said heatinguntil a conversion of 3-rnethy1pyridine-hydrochloride to nicotinic acidof about 14% has been obtained, thereafter separating nicotinic acidfrom said reaction products, and further heating the remaining reactionproducts in the presence of addedchlorine at a temperature of from about80 C. to about 150 C. thereby eifecting the further conversion of at.least a substantial amount of said unconverted 3 methylpyridinehydrochloride to nicotinic acid.

3. The process for the production of nicotinic acid which comprisesheating an admixture of 3 methylpyridine hydrochloride, chlorine andWater at a temperature of from about 50 C. to about 250 0., therebyconverting said admixture to reaction products comprising nicotinic acidand unconverted 3 methylpyridine hydrochlo- 8 ride, continuing saidheating ,until a conversion of 3-methylpyridineehydrochloride :tonicotinic acid of about 14% has ,beenobtained, thereafter separatingnicotinic acid from said vreaction products, and further heating theremainingzreaction products in :the presence of added chlorine. atriatemperature of about C. to about 250 0.

thereby effecting the further conversion :of at least a substantialamount of said unconverted 3-methylpyridine-hydrochloride to. nicotinic:acid.

WILLEM FREDERHi ENGEL, HAN HOOG.

REFERENCES CITED The following references are of record in the file ofthis patent:

Number

1. THE PROCESS FOR THE PRODUCTION OF NICOTINIC ACID WHICH COMPRISESHEATING AN ADMIXTURE OF 3-ETHYLPYRIDINE HYDROCHLORIDE, CHLORINE ANDWATER AT A TEMPERATURE OF ABOUT 115*C., THEREBY CONVERTING SAIDADMIXTURE TO REACTION PRODUCTS COMPRISING NICOTINIC AND UNCONVERTED3-METHYLPYRIDINE HYDROCHLORIDE, CONTINUING SAID HEATING UNTIL ACONVERSION OF 3-METHYLPYRIDINE HYDROCHLORIDE TO NICOTINIC ACID OF ABOUT14% HAS BEEN OBTAINED, THEREAFTER SEPARATING NICOTINIC ACID FROM SAIDREACTION PRODUCTS, AND FURTHER HEATING SAID REMAINING REACTION PRODUCTSIN THE PRESENCE OF ADDED CHLORINE AT A TEMPERATURE OF ABOUT 115*C.,THEREBY EFFECTING THE FURTHER CONVERSION OF AT LEAST SUBSTANTIAL AMOUNTOF SAID UNCONVERTED 3-METHYLPYRIDINE HYDROCHLORIDE TO NICOTINE ACID.